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Supplemental Table 1. Association of clinical features with BM micrometastatic cell burden (CD99+CD45- percent) in flow cytometry cohort. Supplemental Table 2. Total CD99+CD45- percent burden in Ewing sarcoma patients with clinically evident BM metastasis (N=6).

Purpose: Flow cytometry and RT-PCR can detect occult Ewing sarcoma cells in the blood and bone marrow. These techniques were used to evaluate the prognostic significance of micrometastatic disease in Ewing sarcoma.Experimental Design: Newly diagnosed patients with Ewing sarcoma were enrolled on two prospective multicenter studies. In the flow cytometry cohort, patients were defined as “positive” for bone marrow micrometastatic disease if their CD99+/CD45− values were above the upper limit in 22 control patients. In the PCR cohort, RT-PCR on blood or bone marrow samples classified the patients as “positive” or “negative” for EWSR1/FLI1 translocations. The association between micrometastatic disease burden with clinical features and outcome was assessed. Coexpression of insulin-like growth factor-1 receptor (IGF-1R) on detected tumor cells was performed in a subset of flow cytometry samples.Results: The median total bone marrow CD99+CD45− percent was 0.0012% (range 0%–1.10%) in the flow cytometry cohort, with 14 of 109 (12.8%) of Ewing sarcoma patients defined as “positive.” In the PCR cohort, 19.6% (44/225) patients were “positive” for any EWSR1/FLI1 translocation in blood or bone marrow. There were no differences in baseline clinical features or event-free or overall survival between patients classified as “positive” versus “negative” by either method. CD99+CD45− cells had significantly higher IGF-1R expression compared with CD45+ hematopoietic cells (mean geometric mean fluorescence intensity 982.7 vs. 190.9; P < 0.001).Conclusions: The detection of micrometastatic disease at initial diagnosis by flow cytometry or RT-PCR is not associated with outcome in newly diagnosed patients with Ewing sarcoma. Flow cytometry provides a tool to characterize occult micrometastatic tumor cells for proteins of interest. Clin Cancer Res; 22(14); 3643–50. ©2016 AACR.

BackgroundXL092 is a novel oral multi-targeted inhibitor of receptor tyrosine kinases. In preclinical studies, oral dosing with XL092 resulted in pharmacodynamic inhibition of MET, TAM kinases (AXL, MER), and VEGFR2 phosphorylation and was associated with significant anti-tumor activity in xenograft tumor models. Drugs targeting TAM kinases may promote an immune-permissive environment, which may enhance response to immune checkpoint inhibitors (ICIs). The combination of XL092 and anti–PD-1 ICI exhibited greater anti-tumor activity in a syngeneic tumor model than either agent alone.[1] Preliminary XL092 pharmacokinetic data indicate a median terminal half-life of 21 hours, suitable for daily dosing.MethodsThis multi-center, phase 1, open-label study aims to enroll approximately 800 patients total in dose-escalation and cohort-expansion stages (NCT03845166). The dose-escalation stage will enroll patients with inoperable locally advanced or metastatic solid tumors in a 3+3 design (monotherapy cohorts) or rolling 6 design (combination cohorts). Patients will receive escalating doses of XL092 alone or in combination with ICIs (atezolizumab 1200mg Q3W or avelumab 800mg Q2W). Following identification of the maximum tolerated dose (MTD) and/or recommended dose (RD) of XL092 monotherapy, the expansion stage will enroll XL092 monotherapy cohorts in 3 tumor-specific indications (renal cell carcinoma [RCC], metastatic castration-resistant prostate carcinoma [mCRPC], and hormone-receptor positive breast carcinoma [HR+ BC]) using a Simon’s optimal 2-stage design. Once the MTDs/RDs are identified for XL092 in combination with each ICI, the expansion stage will also enroll patients in tumor-specific cohorts for XL092+atezolizumab (RCC, mCRPC, HR+ BC, and colorectal carcinoma) and XL092+avelumab (urothelial carcinoma) using Simon’s optimal 2-stage design or a Precision-Based design. A limited number of patients will be enrolled in dedicated biomarker cohorts, with tumor and blood samples collected, to evaluate the pharmacodynamic effects of XL092 alone and in combination with ICIs. Key eligibility criteria include unresectable or metastatic solid tumors; measurable disease per RECIST 1.1 (expansion cohorts only); available tumor tissue (archival or fresh biopsy); and ECOG 0-1. The primary objective of the dose-escalation stage is to determine MTDs/RDs of XL092 when administered alone or in combination with ICIs, and the primary objective of the expansion stage is to evaluate objective response rate and progression-free survival rate by investigator per RECIST 1.1 of XL092 as monotherapy or in combination with ICIs. Secondary objectives include evaluation of the safety of XL092 alone and in combination with ICIs and evaluation of plasma pharmacokinetics of XL092 and its potential metabolites. The study is open for enrollment.AcknowledgementsMedical writing support provided by Griselda Zuccarino-Catania, PhD (Exelixis, Inc.)Trial RegistrationNCT03845166ReferencesHsu J, Chong C, Goon L, et al. XL092, a Multi-targeted Inhibitor of MET, VEGFR2, AXL and MER with an Optimized Pharmacokinetic Profile. European Journal of Cancer [abstract 33] 2020;138 Suppl 2:S16.Ethics ApprovalStudy approved by institutional Review Boards at each investigational site.

Purpose: Flow cytometry and RT-PCR can detect occult Ewing sarcoma cells in the blood and bone marrow. These techniques were used to evaluate the prognostic significance of micrometastatic disease in Ewing sarcoma. Experimental Design: Newly diagnosed patients with Ewing sarcoma were enrolled on two prospective multicenter studies. In the flow cytometry cohort, patients were defined as “positive” for bone marrow micrometastatic disease if their CD99+/CD45− values were above the upper limit in 22 control patients. In the PCR cohort, RT-PCR on blood or bone marrow samples classified the patients as “positive” or “negative” for EWSR1/FLI1 translocations. The association between micrometastatic disease burden with clinical features and outcome was assessed. Coexpression of insulin-like growth factor-1 receptor (IGF-1R) on detected tumor cells was performed in a subset of flow cytometry samples. Results: The median total bone marrow CD99+CD45− percent was 0.0012% (range 0%–1.10%) in the flow cytometry cohort, with 14 of 109 (12.8%) of Ewing sarcoma patients defined as “positive.” In the PCR cohort, 19.6% (44/225) patients were “positive” for any EWSR1/FLI1 translocation in blood or bone marrow. There were no differences in baseline clinical features or event-free or overall survival between patients classified as “positive” versus “negative” by either method. CD99+CD45− cells had significantly higher IGF-1R expression compared with CD45+ hematopoietic cells (mean geometric mean fluorescence intensity 982.7 vs. 190.9; P < 0.001). Conclusions: The detection of micrometastatic disease at initial diagnosis by flow cytometry or RT-PCR is not associated with outcome in newly diagnosed patients with Ewing sarcoma. Flow cytometry provides a tool to characterize occult micrometastatic tumor cells for proteins of interest. Clin Cancer Res; 22(14); 3643–50. ©2016 AACR.

Background The prognostic significance of having extraskeletal (EES) versus skeletal Ewing sarcoma (ES) in the setting of modern chemotherapy protocols is unknown. The purpose of this study was to compare the clinical characteristics, biologic features, and outcomes for patients with EES and skeletal ES. Methods Patients had localized ES and were treated on two consecutive protocols using five-drug chemotherapy (INT-0154 and AEWS0031). Patients were analyzed based on having an extraskeletal (n = 213) or skeletal (n = 826) site of tumor origin. Event-free survival (EFS) was estimated using the Kaplan–Meier method, compared using the log-rank test, and modeled using Cox multivariate regression. Results Patients with extraskeletal ES (EES) were more likely to have axial tumors (72% vs. 55%; P 8 cm (9% vs. 17%; P < 0.01), and less likely to be white (81% vs. 87%; P < 0.001) compared to patients with skeletal ES. There was no difference in key genomic features (type of EWSR1 translocation, TP53 mutation, CDKN2A mutation/loss) between groups. After controlling for age, race, and primary site, EES was associated with superior EFS (hazard ratio = 0.69; 95% confidence interval: 0.50–0.95; P = 0.02). Among patients with EES, age ≥18, nonwhite race, and elevated baseline erythrocyte sedimentation rate were independently associated with inferior EFS. Conclusion Clinical characteristics, but not key tumor genomic features, differ between EES and skeletal ES. Extraskeletal origin is a favorable prognostic factor, independent of age, race, and primary site.

BackgroundThe choice of a local control (LC) modality for Ewing sarcoma (EWS) of the femur is controversial. This study aimed to determine the effect of LC modality on tumor LC and patient outcomes.MethodsThe study reviewed the treatment and outcomes for 115 patients who had EWS of the femur treated with similar chemotherapy in three cooperative group trials. Patient outcomes were analyzed according to the LC modality using the log-rank test and the cumulative incidence of local or distant failure using competing risks regression.ResultsThe median age of the patients was 13 years. The most common tumor location was the proximal femur followed by the mid femur. For 55 patients with available data, the tumor was larger than 8 cm in 29 patients and 8 cm or smaller in 26 patients. For 84 patients (73 %), surgery only was performed, whereas 17 patients (15 %) had surgery plus radiation, and 14 patients (12 %) had radiation only. The 5-year event-free survival (EFS) rate was 65 % (95 % confidence interval [CI], 55-73 %), and the 5-year overall survival (OS) rate was 70 % (95 % CI, 61-78 %). Patient outcomes did not differ significantly according to tumor location within the femur (proximal, mid or distal) or tumor size (

5013 Background: Cabozantinib (C), an inhibitor of MET, AXL, and VEGFR, has been shown to promote an immune-permissive environment and has shown promising clinical activity in combination with immune checkpoint inhibitors (ICIs) in solid tumors including renal cell carcinoma and urothelial carcinoma (UC). ICI monotherapy is approved for patients (pts) with locally advanced or metastatic UC with disease progression after platinum-containing chemotherapy. COSMIC-021, a multi-center phase 1b study, is evaluating the combination of C with atezolizumab (A) in various solid tumors (NCT03170960). We report results from Cohort 2 in UC pts with prior platinum-containing chemotherapy. Methods: Eligible pts had ECOG PS 0-1 and had progressed on or after a platinum-containing chemotherapy (including pts with disease recurrences < 12 months after the end of perioperative chemotherapy). Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for first year and Q12W thereafter. The primary endpoint is objective response rate (ORR) per RECIST v1.1 by investigator. Other endpoints include safety, duration of response (DOR), PFS, and OS. Results: As of Dec 20, 2019, 30 pts with advanced UC were enrolled with a median follow-up of 16.5 mo (range 12, 21). Median age was 66 yrs (range 44, 84), 73% were male, and 60% had ECOG PS 1. Primary tumor sites were bladder (80%), renal pelvis (10%), and ureter (10%); the most frequent metastatic sites included lung (40%) and liver (27%). Fourteen pts (47%) had received ≥2 prior systemic anticancer therapies. The most common treatment-related AEs (TRAEs) of any grade were asthenia (37%), diarrhea (27%), decreased appetite (23%), increased transaminases (23%), and mucosal inflammation (20%). Grade 3/4 TRAEs occurred in 57% of pts, with no grade 5 TRAEs. Confirmed ORR per RECIST v1.1 was 27% (8 of 30 pts), including 2 pts with CR. DCR (CR+PR+SD) was 64%. Median DOR was not reached, with the longest DOR ongoing at 14.3+ mos. Median PFS was 5.4 mo (range 0.0+, 17.3+). Conclusions: C in combination with A demonstrated encouraging clinical activity in pts with advanced UC with an acceptable safety profile. Additional cohorts of pts with advanced UC are being explored in the study. Clinical trial information: NCT03170960 .

OBJECTIVES Hepatitis C virus (HCV) infection causes an alteration in T-cell maturation and activation in patients coinfected with human immunodeficiency virus (HIV). Because interleukin 7 (IL-7) is a major cytokine controlling T-cell homeostasis, we analyzed the potential influence of HCV coinfection on circulating IL-7 levels in HIV-infected women before and after highly active antiretroviral therapy (HAART). DESIGN AND METHODS This prospective study included 56 HIV monoinfected, 55 HIV/HCV coinfected without HCV viremia, 132 HIV/HCV coinfected with HCV viremia, and 61 HIV/HCV-uninfected women for whom plasma levels of IL-7 were determined by enzyme-linked immunosorbent assay at 1 or more follow-up visits before and after HAART. Cross-sectional analyses of the associations between plasma IL-7 levels and HCV infection, demographic, clinical, and immunologic characteristics were evaluated using univariate and multivariate linear regression models before and after HAART. RESULTS In multivariate models, IL-7 levels were significantly higher in coinfected HCV viremic women than in HIV monoinfected women (multiplicative effect = 1.48; 95% confidence interval: 1.01 to 2.16; P = 0.04) before HAART, but were similar between these two groups among women after HAART. In addition to HCV viremia, higher IL-7 levels were associated with older age (P = 0.02), lower CD4(+) T-cell count (P = 0.0007), and higher natural killer T-cell count (P = 0.02) in women before HAART. Among HAART-treated women, only lower CD4(+) T-cell count was significantly associated with IL-7 level (P = 0.006). CONCLUSIONS Our data demonstrate that in HIV-infected women, circulating levels of IL-7 are strongly associated with CD4 T-cell depletion both before and after HAART. Our data also demonstrate that HCV viremia increases circulating IL-7 levels before HAART but not after HAART in coinfected women. This suggests that the effect of HCV on lymphopenia is abrogated by HAART.

Background Although multiple prognostic variables have been proposed for Ewing sarcoma (EWS), little work has been done to further categorize these variables into prognostic groups for risk classification. Procedure We derived initial prognostic groups from 2,124 patients with EWS in the SEER database. We constructed a multivariable recursive partitioning model of overall survival using the following covariates: age; stage; race/ethnicity; sex; axial primary; pelvic primary; and bone or soft tissue primary. Based on this model, we identified risk groups and estimated 5-year overall survival for each group using Kaplan–Meier methods. We then applied these groups to 1,680 patients enrolled on COG clinical trials. Results A multivariable model identified five prognostic groups with significantly different overall survival: (i) localized, age